The secretion of growth hormone is known to be regulated by a growth-hormone releasing factor in the hypothalamus and a growth-hormone release inhibiting factor somatostatin. In the case of humans, the growth-hormone releasing factor (hereunder sometimes abbreviated as GHRH) in the hypothalamus is a peptide having about 40 amino acid residues and several types including one separated and purified from human cells and one synthesized with a peptide synthesizer have begun to be used as an in vivo diagnostic or a therapeutic of dwarfism. However, the method involving separation and purification from human cells has the problem of limited productivity whereas the synthesis method which requires condensation of almost 40 amino acids is not only cumbersome in operation but also time-consuming and less cost-effective.
Development and research has therefore been made of peptides that consist of a shorter chain of amino acids, that are easy to synthesize and that promote the secretion of growth hormone. As a result, growth-hormone releasing peptides such as pralmorelin have been developed as therapeutics of hypothalamic or pituitary dwarfism or diagnostics of pituitary functions (JP 7-507039 A (Kohyo) and JP 10-45619 A (Kokai)).
It has been known that those growth-hormone releasing peptides (GHRPs) share no structural homology with GHRH but that their effects on the release of growth hormone are similar, except for the mechanism of actions they exhibit. A recent report also discloses that whereas GHRH has only direct action on the secretion of growth hormone in the pituitary, GHRPs not only directly affect the secretion of growth hormone in the pituitary but also show GHRH secreting action in the arcuate nucleus and somatostatin secretion inhibiting action in the periventricular nucleus.
Thus, because of these differences in structure and mechanism of action, there is a need to study the method of applying GHRPs such as pralmorelin aside from the application method for GHRH. In the past, pralmorelin has primarily been administered as an injection. However, there is a demand for the development of preparations that impose less stress on patients and pralmorelin has recently been shown to be effective in intranasal administration (Journal of Clinical Endocrinology and Metabolism, Vol. 80, No. 10, pp. 2987–2992 (1995), Journal of Endocrinology, 155, pp. 79–86 (1997) and Xenobiotica, Vol. 28, No. 11, 1083–1092 (1998)).
The reported preparations for intranasal administration use physiological saline as a solvent. This is because the preparations for intranasal administration which are applied to the nasal mucosa are commonly rendered isotonic with physiological saline in order to reduce irritation. However, in the case of pralmorelin, the use of physiological saline as a solvent presents the following problems and it is difficult to formulate it pharmaceutically.
To be more specific, pralmorelin has low saturated solubility in physiological saline (0.15 w/v % at 25° C. when it is dihydrochloride) and at higher concentrations, pralmorelin becomes insoluble with the lapse of time and a problem occurs in terms of storage stability, thus making it difficult to formulate pralmorelin pharmaceutically using physiological saline. Even at concentrations lower than its saturated solubility, pralmorelin has low in vivo absorption and needs frequent administration.
Hence, no pralmorelin preparations have ever been made practicable using physiological saline.
In view of these, in order to develop pralmorelin preparations for intranasal administration, it is essential to increase the absorption and concentration of pralmorelin in the preparation and there is an urgent need to develop preparations that are improved in those aspects. It is also indispensable to provide pralmorelin preparations for intranasal administration that ensure high stability over time in practical applications.
An object, therefore, of the invention is to increase the in vivo absorption of pralmorelin.
Another object of the invention is to provide a pralmorelin preparation for intranasal administration having higher concentration than preparations using physiological saline. Since inorganic salts formerly used as osmolarity moderators lower the solubility of pralmorelin, the present inventors made intensive studies including the choice of useful osmolarity moderators other than the inorganic salts.
Still another object of the invention is to obtain industrially feasible pralmorelin containing preparations for intranasal administration and to design practically feasible formulations.